CAREER: Endogenous Signaling Through the Farnesoid X Receptor

职业生涯：通过 Farnesoid X 受体的内源信号传导

• 批准号: 0844801
• 负责人: Gregory Tochtrop
• 金额: $ 89.31万
• 依托单位: Case Western Reserve University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2015-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0844801&HistoricalAwards=false
• 关键词: CAREER; Endogenous; Signaling; Through; Farnesoid

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).Scientific Impacts:This CAREER project aims to understand the complex feedback network between bile acids and their cellular sensor, the farnesoid X receptor (FXR). Bile acids are ubiquitous physiologic small molecules present in all mammals and most vertebrates that play a central role in digestion. Interestingly, when looking across species, the chemical composition of the bile acid pool is quite diverse. Even within a species, there can be significant variability, as seen in humans. The goals of this project are twofold. First, an approach will be developed using nuclear magnetic resonance (NMR) spectroscopy in conjunction with synthetic organic chemistry to develop bile acid probes to understand how these molecules interact with and signal through FXR. Second, these probes will be used to study central questions of bile acid selectivity between FXR and a class of lipid binding proteins that also bind bile acids. As the goals of this research are twofold, so is the global impact. First, this research project will develop NMR as a tool for dissecting complex binding interactions, which will have the effect of expanding the repertoire of tools that can be used by scientists to study such systems. Further, this work will help to illuminate broader questions about the function of FXR and lipid binding proteins as they relate to bile acid homeostasis. Broader Impacts:The pedagogical goals of this project integrate with the research, but focus on biological and chemical education at a more basic and fundamental level. The audience of the described efforts spans from sophomores in high school to sophomores in college and aim to integrate fundamental aspects of both organic chemistry and biochemistry into basic courses at an introductory level. The PI also plans to partner with local high school teachers and integrate their students into scholarly research activities. In addition, a plan is detailed to work with colleagues who are engaged in writing textbooks for introductory classes and local colleagues at Case Western Reserve University to make vertical progress in the way that basic science courses are taught.

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。科学影响：这个职业项目旨在了解胆汁酸和它们的细胞传感器，法内酯X受体（FXR）之间复杂的反馈网络。胆汁酸是一种普遍存在于所有哺乳动物和大多数脊椎动物体内的生理小分子，在消化过程中起着核心作用。有趣的是，当跨物种观察时，胆汁酸池的化学成分是相当多样化的。即使在一个物种内，也可能存在显著的差异，就像在人类身上看到的那样。这个项目有两个目标。首先，将开发一种方法，使用核磁共振（NMR）波谱与合成有机化学相结合来开发胆汁酸探针，以了解这些分子如何与FXR相互作用并通过FXR发出信号。其次，这些探针将用于研究FXR和一类也结合胆汁酸的脂质结合蛋白之间胆汁酸选择性的核心问题。由于这项研究的目标是双重的，因此其全球影响也是双重的。首先，这个研究项目将发展核磁共振作为一种工具来解剖复杂的结合相互作用，这将有扩大工具库的影响，可以被科学家用来研究这类系统。此外，这项工作将有助于阐明FXR和脂质结合蛋白的功能，因为它们与胆汁酸稳态有关。更广泛的影响：该项目的教学目标与研究相结合，但更侧重于基础和基础层面的生物和化学教育。所描述的努力的受众范围从高中二年级到大学二年级，旨在将有机化学和生物化学的基本方面整合到基础课程的入门水平。PI还计划与当地高中教师合作，让他们的学生参与学术研究活动。此外，还详细制定了一项计划，与编写入门课程教材的同事和凯斯西储大学（Case Western Reserve University）的当地同事合作，在基础科学课程的教学方式上取得垂直进展。